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US5952383A - Pharmaceutical composition for oral delivery - Google Patents

Pharmaceutical composition for oral delivery Download PDF

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Publication number
US5952383A
US5952383A US09/029,073 US2907398A US5952383A US 5952383 A US5952383 A US 5952383A US 2907398 A US2907398 A US 2907398A US 5952383 A US5952383 A US 5952383A
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US
United States
Prior art keywords
composition according
oil
composition
diacerein
surfactant
Prior art date
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Expired - Fee Related
Application number
US09/029,073
Inventor
Pierre Metziger
Avraham Cohen
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Negma Steba International Development NV
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Negma Steba International Development NV
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Assigned to NEGMA-STEBA INTERNATIONAL DEVELOPMENT N.V. reassignment NEGMA-STEBA INTERNATIONAL DEVELOPMENT N.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COHEN, AVRAHAM, METZIGER, PIERRE
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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65H—HANDLING THIN OR FILAMENTARY MATERIAL, e.g. SHEETS, WEBS, CABLES
    • B65H23/00—Registering, tensioning, smoothing or guiding webs
    • B65H23/04—Registering, tensioning, smoothing or guiding webs longitudinally
    • B65H23/06—Registering, tensioning, smoothing or guiding webs longitudinally by retarding devices, e.g. acting on web-roll spindle
    • B65H23/10—Registering, tensioning, smoothing or guiding webs longitudinally by retarding devices, e.g. acting on web-roll spindle acting on running web
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B37/00—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding
    • B32B37/14—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by the properties of the layers
    • B32B37/16—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by the properties of the layers with all layers existing as coherent layers before laminating
    • B32B37/22—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by the properties of the layers with all layers existing as coherent layers before laminating involving the assembly of both discrete and continuous layers
    • B32B37/223—One or more of the layers being plastic
    • B32B37/226—Laminating sheets, panels or inserts between two continuous plastic layers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B38/00—Ancillary operations in connection with laminating processes
    • B32B38/18—Handling of layers or the laminate
    • B32B38/1825—Handling of layers or the laminate characterised by the control or constructional features of devices for tensioning, stretching or registration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B2309/00—Parameters for the laminating or treatment process; Apparatus details
    • B32B2309/06—Angles

Definitions

  • the present invention relates to a pharmaceutical composition adapted for oral administration, and more particularly a pharmaceutical composition adapted for an active principle of a medicinal product for human or veterinary use, which is insoluble or sparingly soluble in water and oils, such as diacerein (diacetylrhein), rhein or one of their salts, which allows their bioavalability to be improved.
  • a pharmaceutical composition adapted for oral administration and more particularly a pharmaceutical composition adapted for an active principle of a medicinal product for human or veterinary use, which is insoluble or sparingly soluble in water and oils, such as diacerein (diacetylrhein), rhein or one of their salts, which allows their bioavalability to be improved.
  • Diacerein described in patent FR-A-2,508,798, is a compound whose pharmacological properties have been known for several years and have allowed it to be used as a non-steroidal antiinflammatory medicinal product applicable in the treatment of diseases such as arthrosis.
  • diacerein is virtually insoluble in water and in alcohols, this being a drawback for its administration, in particular by injection.
  • diacerein when it is administered orally, diacerein is not totally absorbed by the digestive tract, and, on account of this incomplete absorption, undesirable side effects may be observed, for example laxative effects.
  • patent EP-A-243,968 describes a water-soluble potassium salt of diacerein which can be used in the preparation of compositions for parenteral administration.
  • Patent EP-A-598,337 describes a composition comprising an active principle of a medicinal product which is insoluble or sparingly soluble in water, incorporated into a crosslinked polymer, a surfactant and an oil, this composition being of improved bioavailability.
  • U.S. Pat. No. 5,225,192 describes a process for preparing a fast-dissolving medicinal product, which consists in incorporating the medicinal product into crosslinked polymer particles which are insoluble but capable of swelling in water, in leaving the product in contact with an organic solvent and in drying under vacuum.
  • the subject of the present invention is a pharmaceutical composition adapted for an active principle of a medicinal product for human or veterinary use, containing a medicinal product which is insoluble or sparingly soluble in water and oils, in particular diacerein, rhein or one of their salts, which can be administered orally and affords faster and more complete absorption of the active principle into the body, and being of better bioavailability, thus making it possible to reduce or eliminate the abovementioned side effects.
  • the subject of the present invention is also a novel pharmaceutical composition based on diacerein, rhein or diacerein or rhein salts, which can be administered orally in the form of a wafer capsule or a gelatin capsule, and which is of improved bioavalability when compared with the usual forms.
  • composition according to the present invention which can be administered orally, containing the abovementioned medicinal product that is insoluble or sparingly soluble in water and oils, selected from diacerein, rhein or one of their pharmaceutically acceptable salts, is essentially distinguished in that it comprises
  • liquid support oil selected from a plant, animal or mineral oil
  • the pharmaceutically acceptable salts which can be used in the invention can be, for example, the sodium or potassium salts of diacerein or of rhein.
  • the liquid support oil used in the composition of the invention can be selected from a plant oil (for example ground-nut oil, soybean oil or sunflower oil), a mineral oil (for example a paraffin) and an animal oil. It can consist of one or more medium-chain triglycerides.
  • the expression "medium-chain” used here with reference to triglycerides means a linear or branched chain preferably comprising between 8 and 12 carbon atoms approximately. Needless to say, it is possible to use one or more triglycerides in combination.
  • the medium-chain triglyceride used in the composition of the invention can be, for example, a fractionated coconut oil.
  • the suspension agent used in the composition can be any oil which is solid or semi-solid at room temperature, and, for example, a hydrogenated plant oil, a wax (for example beeswax) or a gelling agent (for example a silica) .
  • a totally or partially hydrogenated plant oil is preferably used, for example hydrogenated soybean oil.
  • the surfactant can be an anionic or nonionic surfactant but it is preferably a nonionic surfactant chosen from polyalkyl sorbitan esters, polyoxyethylene sorbitan derivatives, and for example a monooleic ester of polyhydroxyethyl sorbitan such as Polysorbate 80 (or Tween 80®), or Span®. These surfactants are well known in the pharmaceutical field and are commercially available.
  • the homogenizing agent can be chosen from the agents currently used in the art. According to the invention, soybean lecithin is preferably used, which has the advantage of exerting both a homogenizing action and a fluidizing action on the components used.
  • composition according to the invention can be adjusted as a function of the desired effects and of the active principle of the medicinal product used.
  • composition comprising between 5 and 25% by weight, preferably between 5 and 10% by weight, of homogenizing agent, and between 5 and 25% by weight, preferably between 10 and 15% by weight, of surfactant, relative to the total weight of the components and of the active principle.
  • the weight ratio between the liquid support oil and the suspension agent is between 8:1 and 2:1, and it is preferably close to 4:1. These two components can be mixed together at room temperature or under hot conditions during the preparation of the composition in order to form a paste or an ointment. The temperature is adjusted as a function of the nature of the components used.
  • the above components are mixed with the active principle of the medicinal product according to the techniques usually used for pharmaceutical preparations, by adding thereto, where appropriate, various common excipients and additives for pharmaceutical formulation.
  • the process is preferably performed in the following way: triglycerides are heated to a temperature of 65°-70° C. approximately, the soybean oil is melted therein and, after cooling to room temperature, the soybean lecithin and a nonionic surfactant are added and the mixture is homogenized in a mixer of standard type, after which the diacerein is added and homogenization of the mixture is continued for 10 to 30 minutes.
  • composition according to the invention can advantageously be in the form of soft gelatin capsules or in the form of hard gelatin capsules, containing, for example, between 20 and 50 mg of active principle per unit.
  • the soft and hard gelatin capsules are prepared according to the usual pharmaceutical techniques and can include, for example, a gelatin-based wall containing various additives such as glycerol, titanium dioxide or iron oxide. It is particularly advantageous for the wall of the gelatin capsules to contain a substance capable of isolating the composition from any source of moisture which might lead to degradation of the active principle.
  • a silicone oil, and for example dimethicone, can be used.
  • the composition according to the invention affords a substantial improvement in the pharmacokinetic properties.
  • composition according to the present invention affords a plasma concentration (C max ) that is markedly increased, more than doubled, in a much shorter time (T max ) since the time falls from 4.3 hours to about 1.3 hours. Furthermore, it is observed that the values of the AUC (area under the curve) are increased by more than 25%.
  • compositions and of pharmaceutical forms for oral administration in accordance with the present invention are given below in order to illustrate the invention without limiting its scope.
  • a composition is prepared containing:
  • This composition is mixed carefully with 38 mg of diacerein in a disk mixer (400 revolutions/min.; 30 min), and encapsulated in the usual manner in capsules based on gelatin, glycerol, purified water and Anidrisorb® supplemented with titanium oxide and iron oxide.
  • a hard gelatin capsule containing a 30 mg dose of rhein sodium salt is prepared using a composition containing:
  • composition is mixed carefully with 30 mg of rhein sodium salt and introduced into hard gelatin capsules with a wall made of gelatin, of the usual commercial type.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Registering, Tensioning, Guiding Webs, And Rollers Therefor (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Pharmaceutical compositions for oral administration are disclosed containing a medicinal product that is insoluble or sparingly soluble in water and oils selected from diacerein, rhein and one of their pharmaceutically acceptable salts.

Description

This case is a 371 of PCT/EP97/03405 filed Jun. 30, 1997.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pharmaceutical composition adapted for oral administration, and more particularly a pharmaceutical composition adapted for an active principle of a medicinal product for human or veterinary use, which is insoluble or sparingly soluble in water and oils, such as diacerein (diacetylrhein), rhein or one of their salts, which allows their bioavalability to be improved.
2. Description of Related Art
Diacerein, described in patent FR-A-2,508,798, is a compound whose pharmacological properties have been known for several years and have allowed it to be used as a non-steroidal antiinflammatory medicinal product applicable in the treatment of diseases such as arthrosis. However, diacerein is virtually insoluble in water and in alcohols, this being a drawback for its administration, in particular by injection. Moreover, when it is administered orally, diacerein is not totally absorbed by the digestive tract, and, on account of this incomplete absorption, undesirable side effects may be observed, for example laxative effects.
Various derivatives, pharmaceutical compositions and pharmaceutical forms intended to improve the properties of diacerein or of other medicinal products which are insoluble or sparingly soluble in water have been described in the literature. Thus, for example, patent EP-A-243,968 describes a water-soluble potassium salt of diacerein which can be used in the preparation of compositions for parenteral administration.
Patent EP-A-598,337 describes a composition comprising an active principle of a medicinal product which is insoluble or sparingly soluble in water, incorporated into a crosslinked polymer, a surfactant and an oil, this composition being of improved bioavailability. U.S. Pat. No. 5,225,192 describes a process for preparing a fast-dissolving medicinal product, which consists in incorporating the medicinal product into crosslinked polymer particles which are insoluble but capable of swelling in water, in leaving the product in contact with an organic solvent and in drying under vacuum.
The subject of the present invention is a pharmaceutical composition adapted for an active principle of a medicinal product for human or veterinary use, containing a medicinal product which is insoluble or sparingly soluble in water and oils, in particular diacerein, rhein or one of their salts, which can be administered orally and affords faster and more complete absorption of the active principle into the body, and being of better bioavailability, thus making it possible to reduce or eliminate the abovementioned side effects.
The subject of the present invention is also a novel pharmaceutical composition based on diacerein, rhein or diacerein or rhein salts, which can be administered orally in the form of a wafer capsule or a gelatin capsule, and which is of improved bioavalability when compared with the usual forms.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The pharmaceutical composition according to the present invention, which can be administered orally, containing the abovementioned medicinal product that is insoluble or sparingly soluble in water and oils, selected from diacerein, rhein or one of their pharmaceutically acceptable salts, is essentially distinguished in that it comprises
a liquid support oil selected from a plant, animal or mineral oil
a suspension agent,
a homogenizing agent,
a surfactant, and
one or more pharmaceutically acceptable excipients or supports.
The pharmaceutically acceptable salts which can be used in the invention can be, for example, the sodium or potassium salts of diacerein or of rhein.
The liquid support oil used in the composition of the invention can be selected from a plant oil (for example ground-nut oil, soybean oil or sunflower oil), a mineral oil (for example a paraffin) and an animal oil. It can consist of one or more medium-chain triglycerides. The expression "medium-chain" used here with reference to triglycerides means a linear or branched chain preferably comprising between 8 and 12 carbon atoms approximately. Needless to say, it is possible to use one or more triglycerides in combination. The medium-chain triglyceride used in the composition of the invention can be, for example, a fractionated coconut oil.
The suspension agent used in the composition can be any oil which is solid or semi-solid at room temperature, and, for example, a hydrogenated plant oil, a wax (for example beeswax) or a gelling agent (for example a silica) . According to the invention, a totally or partially hydrogenated plant oil is preferably used, for example hydrogenated soybean oil.
The surfactant can be an anionic or nonionic surfactant but it is preferably a nonionic surfactant chosen from polyalkyl sorbitan esters, polyoxyethylene sorbitan derivatives, and for example a monooleic ester of polyhydroxyethyl sorbitan such as Polysorbate 80 (or Tween 80®), or Span®. These surfactants are well known in the pharmaceutical field and are commercially available.
The homogenizing agent can be chosen from the agents currently used in the art. According to the invention, soybean lecithin is preferably used, which has the advantage of exerting both a homogenizing action and a fluidizing action on the components used.
The amounts of the various components of the composition according to the invention can be adjusted as a function of the desired effects and of the active principle of the medicinal product used.
In the case of diacerein and rhein, it can be particularly advantageous to use a composition comprising between 5 and 25% by weight, preferably between 5 and 10% by weight, of homogenizing agent, and between 5 and 25% by weight, preferably between 10 and 15% by weight, of surfactant, relative to the total weight of the components and of the active principle.
The weight ratio between the liquid support oil and the suspension agent is between 8:1 and 2:1, and it is preferably close to 4:1. These two components can be mixed together at room temperature or under hot conditions during the preparation of the composition in order to form a paste or an ointment. The temperature is adjusted as a function of the nature of the components used.
The above components are mixed with the active principle of the medicinal product according to the techniques usually used for pharmaceutical preparations, by adding thereto, where appropriate, various common excipients and additives for pharmaceutical formulation.
For example, in the case of a liquid support oil consisting of medium-chain triglycerides and a suspension agent consisting of a hydrogenated soybean oil, combined with soybean lecithin as homogenizing agent, the process is preferably performed in the following way: triglycerides are heated to a temperature of 65°-70° C. approximately, the soybean oil is melted therein and, after cooling to room temperature, the soybean lecithin and a nonionic surfactant are added and the mixture is homogenized in a mixer of standard type, after which the diacerein is added and homogenization of the mixture is continued for 10 to 30 minutes.
The composition according to the invention can advantageously be in the form of soft gelatin capsules or in the form of hard gelatin capsules, containing, for example, between 20 and 50 mg of active principle per unit.
The soft and hard gelatin capsules are prepared according to the usual pharmaceutical techniques and can include, for example, a gelatin-based wall containing various additives such as glycerol, titanium dioxide or iron oxide. It is particularly advantageous for the wall of the gelatin capsules to contain a substance capable of isolating the composition from any source of moisture which might lead to degradation of the active principle. A silicone oil, and for example dimethicone, can be used.
In the case of diacerein, which is virtually insoluble in water and ethanol and sparingly soluble in carbonate solutions and in tetrahydrofuran, the composition according to the invention affords a substantial improvement in the pharmacokinetic properties. In particular, in the case of an oral administration in the form of soft or hard gelatin capsules containing the composition of the invention, an appreciable increase in the rate of dissolution and in the maximum concentration obtained, when compared with a standard composition in the form of a hard gelatin capsule, is observed.
The results of the clinical studies in man, in the case of a composition in capsules containing a 38 mg dose of diacerein, compared with a standard pharmaceutical form (hard gelatin capsule) containing a 50 mg dose of diacerein, are summarized in the table below:
______________________________________
Comparative table
           Hard gelatin capsule
                      Invention
______________________________________
C.sub.max (mg/ml)
             2.07 ± 0.57
                          4.38 ± 1.34
T.sub.max (h)
             4.30 ± 1.65
                          1.30 ± 0.48
______________________________________
It is seen that the composition according to the present invention affords a plasma concentration (Cmax) that is markedly increased, more than doubled, in a much shorter time (Tmax) since the time falls from 4.3 hours to about 1.3 hours. Furthermore, it is observed that the values of the AUC (area under the curve) are increased by more than 25%. These results show that the bioavailability of the active principle used (diacerein) is markedly improved.
Examples of compositions and of pharmaceutical forms for oral administration in accordance with the present invention are given below in order to illustrate the invention without limiting its scope.
EXAMPLE 1
A composition is prepared containing:
______________________________________
medium-chain triglycerides
                   156        mg
hydrogenated soybean oil
                   38         mg
soybean lecithin   14.5       mg
Polysorbate 80     43.5       mg
______________________________________
This composition is mixed carefully with 38 mg of diacerein in a disk mixer (400 revolutions/min.; 30 min), and encapsulated in the usual manner in capsules based on gelatin, glycerol, purified water and Anidrisorb® supplemented with titanium oxide and iron oxide.
EXAMPLE 2
A composition identical to that of Example 1 above, containing 38 mg of diacerein, is encapsulated in gelatin capsules whose wall composition comprises the components indicated in Example 1 as well as 15% by weight approximately of dimethicone.
EXAMPLE 3
A hard gelatin capsule containing a 30 mg dose of rhein sodium salt is prepared using a composition containing:
______________________________________
fractionated coconut oil
                  140         mg
soybean oil       35          mg
soybean lecithin  10          mg
Span ® (sorbitan ester)
                  30          mg
______________________________________
This composition is mixed carefully with 30 mg of rhein sodium salt and introduced into hard gelatin capsules with a wall made of gelatin, of the usual commercial type.

Claims (13)

We claim:
1. Pharmaceutical composition for oral administration containing a medicinal product that is insoluble or sparingly soluble in water and oils, selected from diacerein, rhein and one of their pharmaceutically acceptable salts, comprising:
a liquid support oil selected from a plant, animal or mineral oil,
a suspension agent,
a homogenizing agent,
a surfactant,
and one or more pharmaceutically acceptable expedients or supports.
2. Composition according to claim 1, wherein the liquid support oil is one or more triglycerides with a linear or branched medium chain of 8 to 12 carbon atoms.
3. Composition according to claim 1, wherein the suspension agent is a totally or partially hydrogenated plant oil.
4. Composition according to claim 3, wherein the hydrogenated plant oil is hydrogenated soybean oil.
5. Composition according to claim 1, wherein the surfactant is a nonionic surfactant selected from polyalkyl sorbitan esters and polyoxyethylene sorbitan derivatives.
6. Composition according to claim 1, wherein the homogenizing agent is soybean lecithin.
7. Composition according to claim 1, comprising between 5 and 10% by weight of homogenizing agent and between 10 and 15% by weight of surfactant, relative to the total weight of the components and of an active principle.
8. Composition according to claim 1, wherein the weight ratio between the liquid support oil and the suspension agent is between 8:1 and 2:1.
9. Composition according to claim 1, wherein the composition is in the form of a soft gelatin capsule.
10. Composition according to claim 9, wherein a wall of the soft gelatin capsule contains dimethicone.
11. Composition according to claim 1, wherein the composition is in the form of a hard gelatin capsule.
12. Composition according to claim 11, wherein the wall of the hard gelatin capsule contains dimethicone.
13. Composition according to claim 1, wherein an active principle of a medicinal product is diacerein.
US09/029,073 1996-07-04 1997-06-30 Pharmaceutical composition for oral delivery Expired - Fee Related US5952383A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
NL1003503A NL1003503C2 (en) 1996-07-04 1996-07-04 Pharmaceutical composition for oral administration.
NL1003503 1996-07-04
PCT/EP1997/003405 WO1998001118A1 (en) 1996-07-04 1997-06-30 Pharmaceutical composition for oral delivery

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US (1) US5952383A (en)
EP (1) EP0862423B1 (en)
JP (1) JP4209467B2 (en)
KR (1) KR980009519A (en)
CN (1) CN1196477C (en)
AT (1) ATE275945T1 (en)
AU (1) AU3263197A (en)
BR (1) BR9706537A (en)
CA (1) CA2231342C (en)
DE (1) DE69730688T2 (en)
ES (1) ES2230608T3 (en)
IL (1) IL123336A (en)
MX (1) MX9801727A (en)
NL (1) NL1003503C2 (en)
PL (1) PL189358B1 (en)
WO (1) WO1998001118A1 (en)

Cited By (18)

* Cited by examiner, † Cited by third party
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WO2002058681A2 (en) * 2001-01-23 2002-08-01 Negma-Lerads Use of rhein for preparing a medicine for treating a high level of il-1
US6956048B2 (en) 1999-03-31 2005-10-18 Pharmacia & Upjohn Company Pharmaceutical emulsions for retroviral protease inhibitors
US20060228408A1 (en) * 2003-07-30 2006-10-12 William Charman Drug delivery system
WO2008056156A1 (en) * 2006-11-10 2008-05-15 Sosei R & D Ltd. Salts of dihydroxyanthraquinone carboxylic acids and their therapeutic use
WO2009034558A2 (en) * 2007-09-14 2009-03-19 Wockhardt Research Centre Rhein or diacerein compositions
US20090074856A1 (en) * 2005-12-23 2009-03-19 Cyclacel Limited Crystalline pyrimidine nucleoside derivative suspensions in capsules
FR2920991A1 (en) * 2007-09-14 2009-03-20 Wockhardt Ltd Composition, useful to treat inflammation, preferably osteoarthritis, comprises diacerhein, polyols comprising mannitol, sorbitol, maltitol, maltol, lactitol or xylitol, and optionally excipients comprising e.g. fillers and lubricants
WO2009040776A1 (en) * 2007-09-27 2009-04-02 Wockhardt Research Centre Self-emulsifying pharmaceutical compositions of rhein or diacerein
US20090274773A1 (en) * 2005-11-11 2009-11-05 Cyclacel Limited Antiproliferative combination comprising cyc-682 and a cytotoxic agent
US20100018107A1 (en) * 2008-07-22 2010-01-28 Christensen Kurt L Method and means for controlling the population of mosquitoes in a non-toxic manner
US20100069291A1 (en) * 2006-12-19 2010-03-18 Cyclacel Limited Combination comprising cndac (2'-cyano-2'-deoxy-n4-palmitoyl-1-beta-d-arabinofuranosyl-cytosine) and a cytotoxic agent
US20100285114A1 (en) * 2007-09-27 2010-11-11 Rahul Dabre Pharmaceutical compositions of rhein or diacerein
EP2520285A1 (en) 2007-09-27 2012-11-07 Wockhardt Limited Pharmaceutical compositions of rhein or diacerein
US20140322330A1 (en) * 2010-12-10 2014-10-30 Ns Technologies Pty Ltd Methods for forming miniemulsions and use thereof for delivering bioactive agents
US9549896B2 (en) 2007-06-26 2017-01-24 Drug Delivery Solutions Limited Bioerodible patch comprising a polyaphron dispersion
US9610245B2 (en) 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
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CN1197388A (en) 1998-10-28
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WO1998001118A1 (en) 1998-01-15
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IL123336A (en) 2001-03-19
ATE275945T1 (en) 2004-10-15
CN1196477C (en) 2005-04-13
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DE69730688D1 (en) 2004-10-21
MX9801727A (en) 1998-11-30

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